The core aim of this project is to elucidate the nature, molecular foundations, underlying neurochemistry, and clinical correlates of neural systems-level dysfunction in schizophrenia. The Clinical and Translational Neuroscience Branchs recent efforts have included studies examining pathophysiology and phenotypic heterogeneity in patients carefully studied under both medication-free and treated conditions as well as studies of gene-by-environment interactions relevant to schizophrenia pathogenesis. Under this project, we have advanced comprehensive, multimodal positron emission tomography- and magnetic resonance imaging-based studies of a unique and steadily growing cohort of individuals with schizophrenia who have agreed to be studied under placebo (medication-free) conditions. Though this work is necessarily challenging to conduct, we continue to make progress in data collection, which includes characterization of dopamine-dependent mnemonic and reward-related neural responses, striatal presynaptic dopamine synthetic capacity, and both D1 and D2/3 receptor availability, and neurocognitive functioning. These studies provide the opportunity to better understand illness-related neurobiology in a clinically meaningful context, while accounting for medication effects, and to define contributors to the considerable illness heterogeneity observed in schizophrenia, which may ultimately lead to the development of precision, personalized clinical care. Our recent work integrating assessments of striatal regional cerebral blood flow (rCBF), presynaptic dopamine synthesis, and clinical ratings during blinded antipsychotic monotherapy and placebo conditions permitted identification of robust medication effects on striatal rCBF that correspond with aspects of clinical treatment response and remains an active area of research. We found that variability in both physiological and clinical responses to treatment were predicted by the degree of ventral striatal presynaptic dopaminergic tone present, providing novel insights into potential neurochemical mechanisms underlying heterogeneity in therapeutic response and laying the groundwork for studies currently underway utilizing magnetoencephalography in this cohort (Eisenberg et al, 2017). In parallel efforts to further understand the extraordinary variability present across individuals with schizophrenia spectrum illness, we have also employed clinical ratings-based cluster analyses in a large cohort of individuals with schizophrenia. This work identified three reliable clinical subgroups based on symptom profile low-symptom, deficit, and distress groups which demonstrated distinct patterns of clinical illness severity, cognitive functioning and personality ratings (Dickinson et al, 2018). We found a parallel pattern of results in subgrouping analyses of symptom data from a childhood-onset schizophrenia sample (Craddock et al, 2018). Furthermore, in the adult sample, these subgroups were distinguished by differential frontoparietal neural recruitment during working memory performance, suggesting that clinical distinctions between these groups extend to neurobiology. The importance of this particular phenotype is evident not only in the large body of prior fMRI and PET experimentation from our group characterizing schizophrenia-associated frontoparietal activation abnormalities, but also in our recent collaborative work by demonstrating diminished recruitment of frontoparietal and striatal networks during working memory in inpatients with child-onset schizophrenia (Loeb et al, 2018). Additional sources of heterogeneity in schizophrenia include environmental exposures during development. For instance, obstetric/perinatal complications have been linked with schizophrenia risk, and recent work originating from this Branch has yielded major insights into cumulative genetic risk of illness. We have previously shown that such complications interact with hypoxia-responsive schizophrenia risk genes to affect illness risk, and this year, we report along with collaborators that cumulative effect of the most strongly associated schizophrenia genetic risk loci is greatly amplified in patients with a history of obstetric/perinatal complications (Ursini et al, 2018). In addition, the extent of exposure to urban environments during childhood has previously been found to increase the risk for schizophrenia to a similar extent as obstetric/perinatal complications. We found that a heritable fMRI measurement of dorsolateral prefrontal function was altered in the urban-reared and, furthermore, was differentially predicted by dopamine-related genetic variation in an urbanicity-dependent manner (Reed et al, 2018). These gene-environment interactions are the focus of current research in patients under this project. Ongoing work in these directions will prove important for refining models of illness and antipsychotic treatment and will inform novel therapeutic targeting. This work involves the following studies: NCT00942981, NCT00001258, NCT00024622, NCT00004571, NCT00001247,NCT00001486, NCT00044083, NCT00057707